Lithocholic acid ameliorates ulcerative colitis via the PXR/TLR4/NF-κB/NLRP3 signaling pathway and gut microbiota modulation

作者：Yaoyao Liu, Jie Gao, Lu Chen, Yanfang Chen, Jingjing Jiang, Hong Chen, Li Ma · 发表于：Cellular and Molecular Life Sciences · 年份：2025 · DOI：10.1007/s00018-025-05834-2 · 被引用次数：12 · 研究领域：Inflammatory Bowel Disease、Drug Transport and Resistance Mechanisms、Liver Diseases and Immunity

Ulcerative colitis (UC) is a chronic inflammatory condition of the colon, closely linked to dysbiosis of gut microbiota and imbalances in bile acids. Lithocholic acid (LCA), a secondary bile acid, plays a crucial role in maintaining gut health; however, its specific therapeutic potential in UC remains to be fully elucidated. This study investigates the efficacy of LCA in alleviating UC and explores the underlying mechanisms, particularly focusing on the PXR/TLR4/NF-κB/NLRP3 signaling pathway and gut microbiota modulation. Using a dextran sulfate sodium (DSS)-induced colitis model, our findings demonstrate that LCA administration significantly alleviates colitis symptoms, evidenced by reduced disease activity index (DAI), increased colon length, improved intestinal barrier function, and decreased colonic inflammation. Mechanistically, LCA activates the pregnane X receptor (PXR), which inhibits TLR4-mediated NF-κB/NLRP3 inflammasome activation, leading to reduced colonic inflammation and lower levels of pro-inflammatory cytokines. Furthermore, LCA remodels gut microbiota by promoting beneficial bacterial growth, such as Akkermansiaceae, Lactobacillaceae and Muribaculaceae, while suppressing pathogenic and opportunistic pathogens, including Enterobacteriaceae and Bacteroidaceae. The gut microbiota-dependent effects of LCA were corroborated through antibiotic treatment and fecal microbiota transplantation (FMT) experiments. Notably, the absence of intestinal flora affected PXR ex...